GUANFACINE IN THE TREATMENT OF BORDERLINE PERSONALITY DISORDER

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本项目旨在测试盐酸胍法辛（FDA批准的α-2肾上腺素能激动剂）对边缘型人格障碍（BPD）的影响，边缘型人格障碍是一种以情感不稳定、冲动攻击、认知-知觉障碍和不稳定的人际关系为特征的流行性和致残性疾病。BPD的可用治疗方法因其可变和有限的疗效而臭名昭著，并且这些治疗中的许多治疗具有躯体毒性和/或精神恶化的显著风险。胍法辛是一种安全的药物，已用于身体脆弱的人群，包括儿童（注意力缺陷多动障碍）和医学上受损的成人（高血压，FDA批准）。通过刺激前额叶皮层中的α-2肾上腺素受体，胍法辛已被证明可以增强注意力并减少行为失调。我们相信胍法辛代表了BPD的一种重要的、新颖的和有希望的治疗，因为它有可能改善该障碍的核心障碍之一-前额叶皮层（特别是眶额叶皮层）对情感和行为的相对低活性或无效的调节，导致杏仁核/边缘系统产生的情绪与高级大脑中心的“自上而下”控制之间的不平衡。 假设： 第一章 与安慰剂相比，胍法辛可减少边缘型人格障碍患者的冲动性攻击症状，改善情绪不稳定性。 （二） 与健康对照受试者相比，边缘患者将显示基线时OFC的活性降低和杏仁核的活性增加。与对照组相比，边缘患者对负面图片的反应会显示出增强的惊吓眨眼修饰。与其他额叶功能（例如空间工作记忆任务）相比，边缘患者将在特别利用OFC功能（例如时间感知任务）的认知任务中表现出缺陷。 第三章 健康的对照受试者将在我们正在研究的感兴趣区域（OFC，杏仁核）中对8周内的情绪图片显示稳定的反应。 四、 与安慰剂相比，胍法辛将增加眶额叶皮层的激活，减少杏仁核的激活，这是通过功能磁共振成像的BOLD反应来测量的，以响应负面情绪图片，并降低负面图片的厌恶程度的主观评级。胍法辛将降低边缘受试者对情绪图片的惊吓眨眼增强幅度，反映出与安慰剂相比，杏仁核激活的自上而下控制得到改善。 第五章） 与安慰剂相比，胍法辛将特别改善测试眶额活动的认知任务（例如时间感知任务）的功能，而不是改善利用其他大脑区域（如背外侧前额叶皮层）的认知功能测试（例如空间工作记忆任务）的表现。 探索性假设：（见方案第7页） 第一章 与那些反应更接近我们的健康对照组（例如，对负面情绪刺激的OFC反应更强，对负面刺激的惊吓反应增强更适度）的BPD受试者相比，OFC对负面情绪刺激的活性最低，对负面刺激的惊吓反应增强最高的BPD受试者对胍法辛的反应可能性更低。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project proposes to test the effects of guanfacine hydrochloride, a Food and Drug Administration (FDA)-approved alpha-2 adrenergic agonist, in borderline personality disorder (BPD), a prevalent and disabling disorder characterized by affective lability, impulsive aggression, cognitive-perceptual disturbances and unstable interpersonal relationships. The available treatments for BPD are notorious for their variable and limited efficacy, and many of these treatments carry significant risks of somatic toxicity and/or psychiatric deterioration. Guanfacine is a safe agent that has been used in physically vulnerable populations including children (for attention-deficit hyperactivity disorder) and medically compromised adults (for hypertension, for which it is FDA-approved). By stimulating alpha-2 adrenoreceptors in prefrontal cortex, guanfacine has been shown to enhance attention and reduce behavioral dysregulation. We believe that guanfacine represents an important, novel and promising treatment for BPD in that it has the potential to ameliorate one of the core disturbances of the disorder - relatively hypoactive or ineffective modulation of affect and behavior by the prefrontal cortex (particularly orbital frontal cortex), resulting in an imbalance between emotions arising from the amygdala/limbic system and "top-down" control in higher brain centers. Hypotheses: 1) Guanfacine will decrease impulsive aggressive symptoms and improve emotional lability in borderline personality disorder compared to placebo. 2) Borderline patients will show decreased activity at baseline in OFC and increased activity in amygdala compared to healthy comparison subjects. Borderline patients will show enhanced startle eyeblink modification in response to negative pictures compared to controls. Borderline patients will show deficits in cognitive tasks that particularly tap OFC function (e.g. the time perception task) compared to other frontal lobe function (e.g. a spatial working memory task). 3) Healthy control subjects will show stable responses in the regions of interest we are studying (OFC, amygdala) to emotional pictures over an 8 week period. 4) Guanfacine will increase activation in orbital frontal cortex and decrease amygdala activation as measured by BOLD response with fMRI in response to negative emotional pictures and decrease subjective ratings of the aversiveness of the negative pictures compared to placebo. Guanfacine will decrease the amplitude of the startle eyeblink enhancement to emotional pictures in borderline subjects, reflecting improved top-down control of amygdala activation compared to placebo. 5) Guanfacine compared to placebo will specifically improve function on those cognitive tasks that test orbital frontal activity (e.g. the time perception task) more than it will improve performance on tests of cognitive function that tap other brain regions such as dorsolateral prefrontal cortex (e.g. a spatial working memory task). Exploratory Hypothesis: (see Protocol, p. 7) 1) BPD subjects with the lowest activity in OFC in response to negative emotional stimuli and the highest enhancement of startle response to negative stimuli will be less likely to respond to guanfacine than those with responses that more closely resemble our healthy controls (e.g. more robust OFC response to negative emotional stimuli and more modest enhancement of startle response to negative stimuli).